All publications mentioned throughout this application are fully incorporated herein by reference, including all references cited therein.
A neoplasmic condition is characterized by an abnormal mass of tissue resulting from neoplasia—an abnormal proliferation of cells. It usually causes a lump or tumor. Neoplasms may be benign, pre-malignant (carcinoma in situ) or malignant (cancer). Human cancer diseases such as breast and lung cancers currently claim the lives of millions annually worldwide. Cancer has recently become the leading cause of deaths in the world. Despite aggressive approaches made in the treatments of breast and lung cancers in the past decades, the 5-year survival rate for, e.g., lung cancer remains <15%. Surgery, chemotherapy, and radiation therapy have been generally unsatisfactory, especially in the treatment of advanced diseases. New drugs based on better understanding of the biology of the disease are thus clearly needed to improve the treatment efficacy of various types of malignant cancer.
Natural compounds derived from plant extracts or derivatives of these compounds have been shown to have activity as anti-cancer agents used as growth inhibitors of human cancer cells such as, e.g., paclitaxel, which is used for the treatment of breast and non-small cell lung cancers.
Paclitaxel was discovered by the US National Cancer Institute in 1967 where researches isolated it from the bark of the Pacific yew tree, Taxus brevifolia and named it taxol. The drug was developed commercially by Bristol-Myers Squibb so the generic name was changed to paclitaxel. It has been found in a recent research that paclitaxel acts by inducing Bcl-2 phosphorylation in cancer cells which leads to programmed cell death, as described by Haldar, S. et al., Cancer Res. 56, 1253-1255, 1996. Another example is related to retinoids including natural as well as synthetic derivatives of vitamin A that have been shown to modulate cellular growth as well as differentiation of normal and neoplastic epithelial cells by interacting with nuclear receptors functioning as retinoid-dependent transcriptional factor, as described, e.g., by Amos and Lotan, Methods Enzymol, 190, 217-225, 1990. Retinoic acid most notably is being used to treat some leukemias i.e. PML.
Natural strigolactones of formula I
wherein, e.g., R1 is H, OH or OAc, R2 is H, OH or OAc and R3 is H or methyl are a group of plant hormones that have been implicated in inhibition of shoot branching and as signaling molecules for plant interactions, as described by Dun et al., Trends Plant Sci., 14, 364-372, 2009. These naturally occurring chemicals are a group of closely-related molecules synthesized by most plants possibly using carotenoids as the starting material. Strigolactones trigger germination of parasitic plant seeds (for example Striga from which they gained their name) and stimulate symbiotic mycorrhizal fungi hyphal branching.
An analog of the naturally occurring strigolactones is the synthetic plant hormone (3aR*,8bS*,E)-3-(((R*)-4-methyl-5-oxo-2,5-dihydrofuran-2-yloxy)methylene)-3,3a,4,8b-tetrahydro-2H-indeno[1,2-b]furan-2-one (GR-24), which affects cell cycle in root meristem. This compound, which retains the biological activity of the natural strigolactones, has a potential to be used for induction of germination of parasitic seeds before the desired crop is planted.
Programmed cell death in nature is a common feature in the plant kingdom as a response to environmental cues in multicellular organisms. Examples of programmed cell death in plants are, e.g., leaf abscission in the autumn and hypersensitive response during pathogen attack. Reactive oxygen species have been implicated in the regulation of various types of cell death. However, the precise mechanics of the involvement of reactive oxygen species in the processes leading to initiation of cell death and subsequent containment are currently unknown. The involvement of an Arabidopsis protein GRIM REAPER in the regulation of reactive oxygen species-induced cell death under stress conditions has been demonstrated.
Anti-proliferative agents possess valuable uses that go beyond the very important use in human and animal health, and find applications in plants, yeasts, fungi, etc.
It is an object of the present invention to provide active agents for preventing or inhibiting cell proliferation in a variety of organisms.
It is another object of the invention to provide medicaments comprising strigolactones and strigolactone analogs, which can be advantageously used in the treatment of a variety of cancer conditions, with reduced side-effects compared to known methods and therapies.
Another object of the invention is to provide compositions and medicaments comprising strigolactones and/or strigolactone analogs, as well as use thereof in the treatment of cancer. Said compositions and medicaments may comprise additional anti-cancerous agents, other active agents, and other additives.
In yet another aspect the invention provides methods of treating cancer by administering strigolactones and/or strigolactone analogs.
In addition, the use of the invention alleviates or eliminates undesired side-effects of known cancer treatment.
The above and other objects and advantages of invention will become apparent as the description proceeds.